Dilated cardiomyopathy (DCM) is the most common form of primary cardiac muscle disease, with prevalence estimated at 36.5 cases per 100,000. DCM is characterized by ventricular dilation, decreased myocardial contractility and cardiac output, and increased risk of sudden cardiac death. Ventricular myocytes isolated from failing hearts exhibit changes in expression levels of proteins involved in repolarization of the action potential (AP) and intracellular calcium (Ca2+) cycling. These changes are accompanied by reduction of junctional sarcoplasmic reticulum (JSR) Ca2+ concentration, peak intracellular Ca2+ transient amplitude, slowed diastolic Ca2+ extrusion and prolongation of AP duration. We have previously formulated a "minimal" computational model of the failing canine ventricular myocyte that incorporates experimental data on down-regulation of potassium (K+) currents and the SR Ca2+-ATPase, and up-regulation of the Na+-Ca2+ exchanger. This model is able to qualitatively reconstruct changes in AP and Ca2+ transient morphology observed in failing myocytes. Model simulations predict that down- regulation of the SR Ca2+-ATPase by itself produces significant prolongation of AP duration by reducing JSR Ca2+ level, JSR Ca2+ release and the magnitude of Ca2+-dependent inactivation of L-type Ca2+ current (ICa,L). This decreased Ca2+-dependent inactivation increases ICa,L during the plateau phase, thereby increasing AP duration. These model predictions are supported by results of preliminary experiments. This has led us to hypothesize that JSR Ca2+ level through effects on JSR Ca2+ release and Ca2+-dependent inactivation of ICa.L, modulates AP duration, and that this modulation is important under a range of conditions producing changes in JSR Ca2+ level, including heart failure. The general goal of the proposed research is to test this hypothesis by means of experiments coupled with computational modeling.